Process for preparing oxadiazinediones



United States Patent 3,438,985 PROCESS FOR PREPARING OXADIAZINEDIONESJack Bernstein and Kathryn Alice Losee, New Brunswick, NJ., assignors,by mesne assignments, to E. R. Squibb & Sons, Inc., a corporation ofVirginia N0 Drawing. Continuation-impart of application Ser. No.290,918, June 27, 1963. This application Sept. 22, 1965, Ser. No.489,380

Int. Cl. C07d 87/52; A611; 27/00 U.S. Cl. 260244 3 Ciaims ABSTRACT OFTHE DISCLOSURE This application relates to a process for preparing novel1,2,4-oxadiazinediones of the formula wherein R and R each is a memberof the group consisting of hydrogen and alkyl, R is a member of thegroup consisting of hydrogen, alkyl and B-lower alkyl, and B is a basicnitrogen containing group of less than twelve carbon atoms, and saltsthereof, which comprises cyclizing in the presence of a metal alkoxide acompound of the formula R Ill -NH(H]I IO-GHC 0 O-alkyl wherein thesymbols have the same meaning as described above. The compounds preparedby this process possess anti-convulsant activity.

This application is a continuation-in-part of prior filed application,Ser. No. 290,918, filed June 27, 1963 now U.S. Patent No. 3,238,200.

This invention relates to oxadiazinediones. More particularly, theinvention relates to novel 1,2,4-oxadiazinediones of the formula and tosalts thereof.

The symbols R and R in Formula I represent hydrogen and alkyl,especially lower alkyl groups such as methyl, ethyl, propyl, isopropyl,butyl, isobutyl, t-butyl, amyl and the like.

R represents hydrogen, alkyl and B-lower alkyl. B repsents basicnitrogen containing groups of less than twelve carbon atoms such asamino, lower alkylamino, e.g., methylamino, ethylamino, isopropylamino,and so forth, dilower alkylamino, e.g., dimethylamino, diethylamino,dipropylamino, and so forth, and 5 to 7-membered nitrogen hetrocyclicsincluding piperidino, piperazino, N -lower alkylpiperazino, e.g., N-methylpiperazino, N -hydroxylower alkyl-piperazino, e.g., N-hydroxyethylpiperazino, N -lower alkoxy-lower alkyl-piperazino, e.g., N-methoxyethylpiperazino, morpholino, pyrrolidino, homopiperazino,thiamorpholino, and the like.

The preferred compounds of Formula I are those where- Patented Apr. 15,1969 in R and R both represent hydrogen and R represents hydrogen orlower alkyl.

The new compounds of this invention are produced by cyclizing a compoundof the formula wherein the symbols have the same meaning as definedabove, by treatment with methyl alkoxide, preferably an alkali metallower alkoxide such as sodium methoxide, potassium ethoxide or sodiumpropoxide at ambient temperatures, e.g., 20 to 30 C.

The ureidooxy compounds of Formula II are novel conllpounds which may bederived from acids of the formu a (III) R preferably in acid solution.When R is hydrogen, this reaction may be eflfected by using a metalisocyanate, e.g., an alkali metal compound such as potassium isocyanate,in acid solution. When R is hydrogen, the intermediate of Formula II maybe cyclized and then the alkyl or B-lower alkyl group represented by Ris introduced into the 4- position of the completed ring by reactionwith the halide R -hal in basic solution, e.g., alkali metal hydroxidesuch as sodium hydroxide.

The new compounds of this invention form salts. When at least onenitrogen atom of the ring system is unsubstituted, that is, either R orR is hydrogen or R and R both are hydrogen, the compounds will formmetal salts with strong bases, e.g., alkali metal salts, such as thesodium salt, or alkaline earth metal salts, such as the calcium salt.If, however, R represents a basic group, the compounds will form acidaddition salts with strong acids, e. g., miner-a1 acid salts, such ashydrohalic acid salts like the hydrochloride or hydrobromide, sulfates,nitrates and the like.

The new compounds of Formula I are useful as anticonyulsants. They maybe administered orally or parenterally in conventional dosage forms suchas tablets, capsules, in-jectables and the like by incorporating theoxadiazinedione or a pharmacologically acceptable salt thereof inconventional preparations.

The following examples are illustrative of the invention. Alltemperatures are in degrees centigrade.

EXAMPLE 1 (a) Hydroxylamine-O-acetic acid, ethyl ester hydrochlorideHydrogen chloride gas (200 g.) is passed through a suspension of 55 g.(0.26 M) of hydroxylamine-O-acetic acid hemihydrochloride (Org. Syn. 27,p. 15) in 500 ml. of absolute alcohol at 0 until the alcohol issaturated. The mixture is allowed to come to room temperature, refluxedfor one hour and allowed to cool overnight. The solid is filtered andwashed with ether to yield 62 g. of product melting at 108l0-9. Afterrecrystallization from alcohol-ether, the pure product melts at 110-ll2.

(b) Ureidooxyacetic acid, ethyl ester A solution of 7.7 g. (0.05 M) ofhydroxylamine-O- acetic acid, ethyl ester, hydrochloride, 4 g. (0.05 M)of potassium isocyanate and 100 ml. of Water is evaporated to dryness ona steam bath (2 /2 hours). The residual 10.5 g. of solid isrecrystallized from 30 ml. of water to yield 5 g. (62%) of productmelting at '119-120.

The ureidooxyacetic acid ethyl ester is hydrolyzed in aqueous ethanolcontaining sodium hydroxide. The mixture is acidified with hydrochloricacid, concentrated to dryness and extracted with acetonitrile to removethe inorganic salts. Evaporation of the acetonitrile solution gives thedesired ureidooxyacetic acid.

(c) 2H-1,2,4-oxadiazine-3,5- (4H,6H)-dione To a solution of 3.9 g. (0.17M) of sodium in 500 ml. of absolute alcohol are added 28 g. (0.17 M) ofureidooxyacetic acid ethyl ester. A white flocculent precipitate formsimmediately. The mixture is stirred for 2 hours at room temperature andthe solid is filtered to yield 23 g. of the sodium salt of2H-1,2,4-oxadiazine 3,5 (4H,6H)- dione. This is dissolved in 100 ml. ofwater, cooled and made strongly acid with 20% hydrochloric acid. Thewhite crystalline precipitate is filtered to yield 8 g. (40%) of productmelting at -171173. Recrystallization from 160 ml. of acetonitrileyields 6 g. of pure product which melts at 173175.

EXAMPLE 2 (a) 2-(aminoxy)propionic acid hydrochloride To a solution of98 g. (1.5 M) of potassium hydrochloride in 1 liter of absolute alcoholare added 103 g. (0.75 M) of benzohydroxamic acid. To this suspension isadded a solution of 136 g. (0.75 M) of ethyl a-brompropionate in 500 ml.of absolute alcohol. The resulting mixture is allowed to stand 24 hours.The solid is filtered off and the filtrate is concentrated under reducedpres sure. The viscous residue is extracted with 300 ml. of 80% alcoholand the extract is made slightly acid with 10% H 50 The K SO is filteredoff and the filtrate evaporated. The residue is heated with 1 liter of5% HCl on a steam bath for 2 hours. On cooling, benzoic acidprecipitates, the precipitate is filtered off and the filtrateconcentrated to dryness. The residue is extracted with 1 liter ofabsolute alcohol; a small amount of insoluble material is filtered offand the filtrate again evaporated to dryness. The viscous residue isdissolved in 200 ml. of absolute alcohol and anhydrous ether addedslowly. The crystalline solid which precipitates is filtered and weighs45 g. (43% melting at 155-160. Recrystallization from alcohol-etheryields the pure compound, melting at 166- 168.

(b) 2-(aminoxy)propionic acid, ethyl ester hydrochloride A solution of35 g. (0.24 M) of 2-(aminoxy)propionic acid hydrochloride in 800 ml. ofabsolute alcohol is saturated with HCl gas 190 g.) at 0. The solution isallowed to come to room temperature, refluxed 1 hour, and allowed tostand overnight. The alcohol is removed under reduced pressure and theviscous residue is triturated with dry ether to yield 14 g. (35%) ofproduct melting at 79- 81. After recrystallization from alcohol-etherthe pure product melts at 85-87".

(0) 2-ureidooxypropionic acid ethyl ester A solution of 8.5 g. (0.05 M)of 2-(aminoxy)propionic acid ethyl ester, 4 g. (0.05 M) of potassiumisocyanate and 100 ml. of water is evaporated to dryness on a steambath. The crystalline residue (115 g.) is extracted with 80 ml. of hotacetone. The acetone is evaporated and the viscous residue is trituratedwith hexane to yield 4 g. (46%) of crystalline solid melting at 6062.Recrystallization from acetone-hexane yields pure product melting at6264.

(d) 6-rnethyl-2H-1,2,4-oxadiazine-3,5-(4H,6H)-d-ione To a solution of1.6 g. of sodium (0.07 M) in ml. of absolute alcohol is added a solutionof 12 g. (0.07 M) of 2-ureidooxypropionic acid ethyl ester in 50 ml. ofabsolute alcohol. A gelatinous precipitate forms immediately. Thereaction mixture is stirred at room temperature for 2 hours; then thesolid is filtered to yield 6 g. of sodium salt. The salt is dissolved in200 m1. of water and stirred for 45 minutes with 20 ml. of a wet slurryof Amberlite I'Rl24 ion exchange resin (H cycle) [nuclear sulfoniccation (polystyrene-divinylbenzene) resin]. The mixture is filtered andlyophylized to yield 4 g. of a fluffy solid melting at -125. Aftersublimation at (oil bath) and 2 mm., the pure compound melts at 143145.

EXAMPLE 3 (a) Hydroxylamine-O-acetic acid, methyl esterhydrochloride.-Hydrogen chloride gas is passed through a suspension of55 grams of hydroxyl-amine-O acetic acid hemihydrochloride in 500 ml. ofanhydrous methanol at 0 until the alcohol is saturated. The mixture isallowed to come to room temperature, refluxed for one hour and thenallowed to cool overnight. The reaction mixture is diluted with an equalvolume of ether. The precipitated solid is filtered and washed withether to yield the desired product.

'(b) Acetaldehydeoxime-O-acetic acid, methyl ester. A mixture of 20grams of acetaldehyde and 25.5 grams of hydroxylamine-o acetic acid,methyl ester hydrochloride is suspended in 100 ml. of anhydrous pyridineand is kept at room temperature for 2 hours. One hundred ml. of methanolis added and the reaction mixture is heated to gentle reflux for anadditional 2 hours. The solvents are then removed by concentration underreduced pressure and the residue triturated with 200 ml. of ice-Water.The solution is saturated with sodium chloride and extracted severaltimes with ether. The ether extracts are dried over anhydrous sodiumsulfate, filtered and concentrated. The residue is purified bydistillation under reduced pressure.

(0) N-ethylhydroxylamine-O-acetic acid, methyl ester, hydrochloride.To asolution of 10 grams of acetaldehyde oxime-O-acetic acid, ethyl ester in50 ml. of anhydrous methanol is added 2 grams of palladium on carbon(5%) and the mixture treated with hydrogen at 50 lbs./ sq. in. in a ParrHydrogenator. When the absorption of hydrogen is complete, the reactionmixture is filtered, diluted with anhydrous ether and treated withethereal hydrogen chloride. The precipitated product is filtered andwashed with anhydrous ether.

(d) N'-ethylureidooxyacetic acid, methyl ester.A solution of 8.3 gramsof N-ethylhydroxylamine O-acetic acid, methyl ester hydrochloride, 4.1grams of potassium isocyanate and 100 ml. of water is evaporated todryness on a steam bath. The residue is crystallized from aqueousalcohol to yield the desired product.

(e) 2-ethyl-2H-l,2,4-oxadiazine-3,5-(4H,6H) dione.-- To a solution of4.6 grams of sodium in 500 ml. of anhydrous methanol are added 35.5grams of N'-ethylureidooxy acetic acid, methyl ester, and the reactionmixture stirred at room temperature for 6 hours. The precipitated solid,the sodium salt of 2-ethyl-2H-l,2,4-oxadiazine-3,5- (4H,6H)-dione, isfiltered and washed with anhydrous ether. This sodium salt is thendissolved in 200 ml. of water and the solution is acidified to pH 2 with20% hydrochloric acid. The crystalline precipitate is filtered andwashed with water to yield the desired product. It may be furtherpurified by crystallization from acetonitrile.

EXAMPLE 4 4-methyl-2H-1,2,4-oxadiazine-3,5- (4H,6H -dione (a) N-methylureidooxyacetic acid, ethyl ester.To a solution of 15.5 grams ofhydroxylamine-O-acetic acid, ethyl ester hydrochloride (Example 1a) in100 ml. of pyridine is added dropwise, with vigorous stirring at 5-155.7 grams 'of methyl isocyanate. The reaction mixture is then allowed toWarm to room temperature. After 24 hours the reaction mixture isconcentrated under reduced pressure and the viscous residue trituratedwith cold hexane and then ether. The low melting solid is extracted withhot hexane and hot benzene to yield the desired compound, melting at69-70".

(b) 4-methyl-2H-l,2,4-oxadiazine-3,5-(4H,6H)-dione. To a solution of0.92 grams of sodium in 100 ml. of absolute ethanol is added a solutionof 7 grams of N -methyl ureidooxyacetic acid, ethyl ester in 50 ml. ofabsolute ethanol. The reaction mixture is allowed to stand overnight atroom temperature. The sodium salt of 4-methyl-2H-l,2,4-oxadiazine-3,5-(4H,6H)-dione, which precipitates, is filteredand dissolved in water. It is stirred with 20 ml. of a wet slurry ofAmberlite lR-l24 ion exchange resin (H cycle), filtered and lyophilizedto yield the desired 4-methyl-2H-l,2,4-oxadiazine-3,5-(4H,6H)-dione.

EXAMPLE 5 4-methy1-2I-I-1,2,4-oxadiazine-3 ,5 (4H,6H) -dione To asolution of 1.16 grams of 2H-l,2,4-oxadiaZine-3,5- (4H,6H)-dione in ml.of alcohol there is added 10 ml. of N sodium hydroxide solution.Twograms of methyl iodide are added to the reaction mixture and themixture refluxed gently until neutral. The reaction mixture isconcentrated to remove the alcohol and then treated with Amberlite IR124(H+ cycle) and Amberlite IR45 (OH- cycle) [weak base anion exchangeresin (polystyrene-polyamine)] to remove the inorganic salts.Concentration of the filtrate yields the desired product.

EXAMPLE 6 2-ethyl-4-methyl-2H-1,2,4-oxadiazine-3 5- (4H,6H) -dione (a) N-methyl-N-ethylureidooxyacetic acid, methyl ester.To a solution of 16.5grams of N-ethylhydrooxylamine-O-acetic acid, methyl ester liberatedfrom its hydrochloride (Example 30) in 200 ml. of anhydrous ether thereis added dropwise with vigorous stirring at 515 a solution of 5.7 gramsof methyl isocyanate in 50 ml. of anhydrous ether. The reaction mixtureis allowed to stand overnight at room temperature and is thenconcentrated under reduced pressure to remove the solvent. The productso obtained is sufliciently pure for use in the next step.

(b) ,2-ethyl-4-methyl-2H-l,2,4-oxadiazine-3,5- (4H,6H dione.-To asolution of 1.2 grams of sodium in 50 ml. of anhydrous methanol there isadded 11.1 grams of N methyl-N'-ethylureidooxyacetic acid, methyl ester.The reaction mixture is warmed for two hours at 50 and is thenconcentrated under reduced pressure. The residue is dissolved in water,treated with Amberlite IR-124 ion exchange resin (acid cycle), andfiltered. The filtrate is lyophilized to yield the desired product.

EXAMPLE 7 2-ethyl-6-methy1-2H-1,2,4-oxadiazine-3,5- (4H, 6H) -dioneFollowing the procedure of Example 3 but substituting Z-aminoxypropionicacid hydrochloride (Example 2a) for an equivalent amount ofhydroxylamine-O-acetic acid hemihydrochloride there is obtained2-ethy1-6-methyl-2H- l,2,4-oxadiazine-3,5-(4H,6H)-dione.

EXAMPLE 8 4,6-dimethyl-2H-l,2,4-oxadiazine-3,5-(4H,6H)-di0ne Followingthe procedure of Example 4 but substituting an equivalent amount of2-(aminoxy)propionic acid, ethyl ester hydrochloride (Example 212) forthe hydroxylamine- 6 O-acetic acid, ethyl ester hydrochloride, there isobtained the desired 4,6-dimethyl-2I-I-1,2,4-oxadiazine 3,5 (4H,6H)-dione.

EXAMPLE 9 2-ethyl-4-n-propyl-6-methyl-2H- l ,2,4-oxadiazine-3,5-

(4H,6H) -dione (a) 2-(ethylaminoxy) propionic acid, methyl esterhydrochloride.-Following the procedure of Example 3a, b and c butsubstituting an equivalent of 2-(aminoxy)propionic acid, hydrochloride(Example 2a) for the hydroxylamine- O-acetic acid hemihydrochloride inExample 3a there is obtained 2-(ethylaminoxy)propionic acid, methylester hydrochloride.

(b) 2-N'-ethyl N propylureidooxy)propionic acid, methyl ester.-To asolution of 18.3 grams of 2-(ethylaminoxy)propionic acid, methyl esterhydrochloride in 100 ml. of anhydrous pyridine is added dropwise, withvigorous stirring at 5-15", 8.5 grams of n-propyl isocyanate. Thereaction mixture is then allowed to warm to room temperature and after24 hours is concentrated under reduced pressure. The viscous residue istriturated with hexane and ether and is then extracted with hot benzene.Concentration of the benzene extract yields the desired product.

(c) 2-ethyl-4-n-propyl-6-methyl-2H-1,2,4 oxadiazine-3,5-(4H,6H)-dione.-To a solution of 1.2 grams of sodium in 50 ml. ofanhydrous methanol, there is added 12 grams of 2- (N-ethyl-N-propylureidooxy) propionic acid, methyl ester. The reaction mixture isrefluxed for 3 hours and is then concentrated under reduced pressure.The residue is dissolved in water, treated with Amberlite IR- 124 ionexchange resin (acid cycle) and then filtered. Concentration of thefiltrate yields the desired product.

EXAMPLE l0 4- 3-dimethylaminopropyl) -6-methyl-2H- 1 ,2,4 oxadiazine-3,5(4H, 6H) -dione To a suspension of 24 grams of a 50% sodium hydridedispersion (in oil) in 250 ml. of toluene there is added 6.5 grams of6-methyl-2H 1,2,4 oxadiazine-3,5-(4H,6H)- dione. After one hour stirringat room temperature, during which time the original vigorous evolutionof hydrogen has essentially ceased, the reaction mixture is treateddropwise with a solution of 6.8 grams of dimethylaminopropyl chloride in100 ml. of toluene. The reaction mixture is heated to and maintained atthis temperature for 3 hours. The reaction mixture is cooled, filteredto remove the inorganic salt, and extracted with 10% hydrochloric acid.The acid extract is neutralized, saturated with sodium chloride andextracted with ether. Concentration of the ether extract yields thedesired product.

The product may be converted to pharmaceutically accepted salts bytreatment of an ether solution of the base with an ethereal or alcoholicsolution of the pharmaceutically accepted acid and recovering the saltby filtration or concentration.

EXAMPLE 11 By substituting for the dimethylaminopropyl chloride inExample 10 equivalent proportions of 3-morpholinopropyl chloride2-(4methylpiperazino)-ethyl chloride or 2-(homopiperazino)ethylchloride, respectively, there are obtained 6-methyl-4-(3-morpholinopropyl) -2H-1,2,4-oxadiazine-3,5- (4H,6H) -dione, 4 [2-4-methylpiperazino ethyl] -6-methyl-2H-1,2,4-oxadiazine-3,5- (4H,6H)-dione and 4-[2-(homopiperazino)ethyl 6methyl-2H-1,2,4-oxadiazine-3,5-(4H, 6H)-dione.

7 What is claimed is: 1. A process for the production of a compoundhaving the formula R-HO NR O= CZO N is wherein R and R each is a memberof the group consisting of hydrogen and lower alkyl, R is a member ofthe group consisting of hydrogen, lower alkyl and B- lower alkyl, and Bis a basic nitrogen containing group of less than twelve carbon atomsselected from the group consisting of amino, lower :alkyl amino, diloweralkyl amino, 5- to 7-membered nitrogen-containing heterocyclics selectedfrom the group consisting of piperidino, piperazino, N -loweralkylpiperazino, N -hydroxy-lower alkylpiperazino, N -lower alkoxy-loweralkylpiperazino, morpholino, pyrrolidino and thiamorpholino; and saltsthereof, which comprises cyclizing in the presence of a alkali metalalkoxide a compound of the formula wherein the symbols have the samemeaning as described above.

2. A process for the production of a compound of the formula lower alkylwhich comprises cyclizing in the presence of an alkali metal alkoxide acompound of the formula 3,251,838 5/1966 Kalm 260244 HENRY R. JILES,Primary Examiner. R. T. BOND, Assistant Examiner.

US. Cl. X.R. 260-999

